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PubMed1997

Oligomerization of the amide sensor protein AmiC by x-ray and neutron scattering and molecular modeling.

AmiC is the negative regulator of the amidase operon which is involved in amide metabolism in the cytosol of Pseudomonas aeruginosa. Crystal structures show that AmiC contains two large domains that are very similar to the periplasmic leucine-isoleucine-valine binding protein (LivJ) of Escherichia coli. Synchrotron X-ray and neutron (in 100% 2H2O buffer) scattering data were obtained for AmiC in the presence of its substrate acetamide and its anti-inducer butyramide which binds more weakly to AmiC than acetamide. Guinier analyses to obtain radius of gyration RG and molecular weight Mr values showed that AmiC formed trimers whose formation was favored in the presence of acetamide and which exhibited concentration-dependent properties at concentrations between 0.4 and 2 mg/mL. Above 2 mg/mL, where trimers predominated, the RG data were identical within 0.05 nm for AmiC-acetamide and AmiC-butyramide with mean X-ray and neutron RG values of 3.35 and 3. 28 nm, respectively. Scattering curve fits constrained by the crystal structure of AmiC-acetamide were evaluated in order to describe a model for trimeric AmiC. A translational search of parallel alignments of three monomers to form a symmetric AmiC homotrimer gave a good X-ray curve fit. Combinations of calculated curves for monomeric, dimeric, trimeric, and tetrameric AmiC as seen in the crystal structure of AmiC gave reasonable but weaker X-ray curve fits which did not favor the existence of tetrameric AmiC. It is concluded that AmiC exhibits novel ligand-dependent oligomerization properties in solution when these are compared to other members of the periplasmic binding protein superfamily, where AmiC exists in monomeric and trimeric forms, the proportions of which depend on the presence of acetamide or butyramide.

Bacterial Proteins↗
PubMed1991

Mean residence times and distribution volumes for drugs undergoing linear reversible metabolism and tissue distribution and linear or nonlinear elimination from the central compartments.

Equations for the mean residence times in the body (MRT) and in the central compartment (MRTc) are derived for bolus central dosing of a drug and its metabolite which undergo linear tissue distribution and linear reversible metabolism but are eliminated either linearly or nonlinearly (Michaelis-Menten kinetics) from the central compartments. In addition, a new approach to calculate the steady-state volumes of distribution for nonlinear systems (reversible or nonreversible) is proposed based on disposition decomposition analysis. The application of these equations to a dual reversible two-compartment model is illustrated by computer simulations.

Computer Simulation↗
PubMed1996

Influence of surface free energies and cohesion parameters on pharmaceutical material interaction parameters-theoretical simulations.

PURPOSE: The aim of this study was to perform simulations of the influence of surface free energies and cohesion parameters on various interaction parameters within binary systems. METHODS: Using predictive equations derived from surface free energies and cohesion parameters originally proposed by Wu (2, 3) and by Rowe (4), values of interfacial tension, spreading and reduced spreading coefficients, interaction parameter and strength of interaction were simulated by means of a data processor. The influence of polar and disperse fractions of the two interacting materials was also examined. RESULTS: From the simulations, boundary conditions could be drawn: minimum interfacial tension, positive spreading coefficient, reduced spreading coefficient superior to unity, maximum value of the interaction parameter or of the strength of interaction. CONCLUSIONS: Simulations of the various parameters will help the formulator to select proper materials, eg. an agent that will efficiently bind some powdered substrate, a film-forming agent that will properly coat given cores or a material that will enhibit high interaction with a substrate.

Biocompatible Materials↗
PubMed1997

Bayesian population pharmacokinetic and pharmacodynamic analyses using mixture models.

Population studies of the pharmacokinetics or pharmacodynamics of drugs help us, learn about the variability in drug disposition and effects, information that can be used to treat future patients at safe and effective doses. We present a new approach to population modeling based on a weighted mixture of normal distributions having random weights and means. This method allows estimation of underlying continuous population distributions without prespecifying the parametric form or shape of these probability distributions. Additionally, this method can carry out nonparametric regression of pharmacokinetic or dynamic parameters on patient covariates while estimating the underlying distributions. Two examples illustrate the method and its flexibility.

Bayes Theorem↗
PubMed2003

[Prospective analysis of quantification of contrast media enhanced power Doppler sonography of equivocal breast lesions].

PURPOSE: To evaluate the potential diagnostic value of quantification of contrast enhanced power Doppler sonography in breast lesions. MATERIALS AND METHODS: Before and after bolus application of 300 mg/ml of the contrast agent Levovist (Schering, Germany), 76 randomly selected equivocal breast lesions (37 benign, 39 malignant) underwent power Doppler sonography. The data were acquired with a 7.5 MHz linear array transducer (Sonoline Versa Pro and Sonoline Elegra Plus, Siemens, Germany). Following postprocessing digitalization, color pixel density (CPD) and dynamic contrast enhancement were calculated and compared using different regions of the tumor (entire lesion, center and periphery). RESULTS: A measurable pixel signal prior to the application of the contrast agent was observed in 12 of 37 benign and in 18 of 39 malignant lesions (32.4 % and 46.2 %, respectively). After administration of the contrast agent, the lesions with measurable signal increased to 20 of 37 (54 %) and 25 of 39 (64.1 %), respectively. No statistically significant difference of dignity-related signal intensity could be verified before or after administration of the contrast agent. Maximum CPD and relative increase in pixel density after contrast medium was appreciably higher in the center of malignant lesions than in corresponding regions of benign lesions. CONCLUSION: Quantification of color pixel density is rather nonspecific for the discrimination of equivocal breast lesions and not suitable for clinical routine. Signal detection and quantification of color coded pixels enable comparison of dynamic contrast enhancement.

Adult↗
PubMed2002

On the simulation of protein folding by short time scale molecular dynamics and distributed computing.

There are proposals to overcome the current incompatibilities between the time scales of protein folding and molecular dynamics simulation by using a large number of short simulations of only tens of nanoseconds (distributed computing). According to the principles of first-order kinetic processes, a sufficiently large number of short simulations will include, de facto, a small number of long time scale events that have proceeded to completion. But protein folding is not an elementary kinetic step: folding has a series of early conformational steps that lead to lag phases at the beginning of the kinetics. The presence of these lag phases can bias short simulations toward selecting minor pathways that have fewer or faster lag steps and so miss the major folding pathways. Attempts to circumvent the lags by using loosely coupled parallel simulations that search for first-order transitions are also problematic because of the difficulty of detecting transitions in molecular dynamics simulations. Nevertheless, the procedure of using parallel independent simulations is perfectly valid and quite feasible once the time scale of simulation proceeds past the lag phases into a single exponential region.

Computer Simulation↗
PubMed1996

Internal packing conditions and fluctuations of amino acid residues in globular proteins.

In order to investigate the environmental conditions of amino acid residues in protein molecules, four kinds of packing studies (atomic, geometric, hydrophobic and hydration) were formulated and tested on two proteins; bovine pancreatic trypsin inhibitor (BPTI) and bovine pancreatic ribonuclease S (RNase S). The inter-relationship of these packings on the fluctuations of amino acid residues was analysed by comparing the packing results with the dynamical studies, such as the root-mean-square-deviation values of atomic displacements obtained from the trajectories of molecular dynamics simulation, temperature factor information from crystal structures and residue fluctuations in proteins from continuum model. These analyses yield information about the most fluctuating and most stabilizing residue sites. Comparison of the results obtained by these methods indicate a good agreement, specifying an inverse correlation between the residue packing and fluctuations. This kind of study is helpful in identifying the specific residue sites such as nucleation, receptor binding and antigenic determining sites which in a way indirectly correlates with the functional residues in protein molecules.

Amino Acids↗
PubMed1997

Fast direct Fourier methods, based on one- and two-pass coordinate transformations, yield accurate reconstructions of x-ray CT clinical images.

The conversion from polar to Cartesian coordinates can be carried out with two-pass algorithms. The paper describes two different methods based on concentric square frames and octagonal frames and their results, obtained with accurate interpolations based on the "moving window Shannon reconstruction' (MWSR). The embedding of these algorithms in direct Fourier methods (DFMs) of tomographic reconstruction is discussed. With respect to one-pass methods and to the use of octagonal frames, the square frame method makes it possible to carry out the first pass, a radial resampling, in the direct space, before computing 1D Fourier transforms (FTs) of projections. Reconstructions of clinical images from the raw data of a third-generation x-ray tomograph are presented and compared with those obtained with one-pass DFMs and with the convolution back-projection method (CBPM) performed by the instrument. The simple algorithm using square frames yields results in complete agreement with other DFM protocols and the CBPM. On a general-purpose computer, the execution of DFM protocols based on one-pass and two-pass coordinate transformations is 35 to 55 times faster than the CBPM and make the algorithms attractive for modern instrumentation.

Algorithms↗
PubMed2002

Estimating and evaluating the statistics of gapped local-alignment scores.

We present a novel maximum-likelihood-based algorithm for estimating the distribution of alignment scores from the scores of unrelated sequences in a database search. Using a new method for measuring the accuracy of p-values, we show that our maximum-likelihood-based algorithm is more accurate than existing regression-based and lookup table methods. We explore a more sophisticated way of modeling and estimating the score distributions (using a two-component mixture model and expectation maximization), but conclude that this does not improve significantly over simply ignoring scores with small E-values during estimation. Finally, we measure the classification accuracy of p-values estimated in different ways and observe that inaccurate p-values can, somewhat paradoxically, lead to higher classification accuracy. We explain this paradox and argue that statistical accuracy, not classification accuracy, should be the primary criterion in comparisons of similarity search methods that return p-values that adjust for target sequence length.

Algorithms↗
PubMed1988

The relationship of intralaboratory bias and imprecision on laboratories' ability to meet medical usefulness limits.

The previously described computer modeling technic empirically develops quantitative relationships between intralaboratory performance, as characterized by individual laboratories' coefficients of variation (CVs) and biases, and clinical "medical usefulness limits." These limits determine the magnitude of total analytic error, the combined effects of CV and bias that can be tolerated by the clinician. The computer model delineates all combinations of CV and bias compatible with specified medical usefulness limits. Both CV and bias are critical in determining a laboratory's ability to meet medical usefulness limits. For example, a laboratory with a 6% CV and zero bias will meet the +/- 10% or less total analytic error (medical usefulness limit) 90% of the time. If the medical usefulness limit is expanded to +/- 15%, a laboratory with a 6% CV can tolerate coexisting relative biases of up to 4% and still meet this limit 95% of the time. Plots of the limiting values for combinations of intralaboratory CV and bias are given that allow the laboratory's results to fall within medical usefulness limits of 2, 5, 10, 15, and 20%.

Clinical Laboratory Techniques↗
PubMed1994

Rapid numerical integration algorithm for finding the equilibrium state of a system of coupled binding reactions.

We have adapted a simple method of numerical integration to predict the equilibrium state of a population of components undergoing reversible association according to the Law of Mass Action. Its particular application is to populations of protein molecules in aqueous solution. The method is based on Euler integration but employs an adaptive step size: the time increment being reduced if it would make the concentration of any component negative and increased while the concentration of any component changes at greater than a specified rate. Parameters of the algorithm have been optimized empirically using a model set of binding equilibria with dissociation constants ranging from 10(-5) M to 10(-9) M. The method obtains the solution to a set of binding equilibria more rapidly than the conventional initial value methods (simple Euler, 4th order Runge-Kutta and variable-step Runge-Kutta methods were tested) for the same accuracy. A computer code in standard C is presented.

Algorithms↗
PubMed1999

Bayesian inference on biopolymer models.

MOTIVATION: Most existing bioinformatics methods are limited to making point estimates of one variable, e.g. the optimal alignment, with fixed input values for all other variables, e.g. gap penalties and scoring matrices. While the requirement to specify parameters remains one of the more vexing issues in bioinformatics, it is a reflection of a larger issue: the need to broaden the view on statistical inference in bioinformatics. RESULTS: The assignment of probabilities for all possible values of all unknown variables in a problem in the form of a posterior distribution is the goal of Bayesian inference. Here we show how this goal can be achieved for most bioinformatics methods that use dynamic programming. Specifically, a tutorial style description of a Bayesian inference procedure for segmentation of a sequence based on the heterogeneity in its composition is given. In addition, full Bayesian inference algorithms for sequence alignment are described. AVAILABILITY: Software and a set of transparencies for a tutorial describing these ideas are available at http://www.wadsworth.org/res&res/bioinfo/

Bayes Theorem↗
PubMed2000

Mathematica packages for simulation of experimental genetics.

UNLABELLED: This note describes add-on packages for the Mathematica software system (Wolfram 1996) which allow simulation and analysis of both Mendelian and complex genetic traits in experimental crosses of plants or animals. AVAILABILITY: The add-on packages are freely available at http://www.mathsource.com/cgi-bin/msitem?0209-30 4. SUPPLEMENTARY INFORMATION: A tutorial notebook file is included with the packages at the mathsource site.

Animals↗
PubMed1986

Steady-state modelling of metabolic pathways: a guide for the prospective simulator.

Steady-state modelling and control analysis by means of computer simulation provides valuable insight into the behavior of metabolic pathways. This review, which is aimed at the newcomer to this field, discusses the objectives of steady-state modelling and the steady-state properties of the four basic metabolic structures, namely linear and branched chains, loops and cycles. It is shown how the model definition in terms of stoichiometric reactions and rate equations leads to a set of balance equations from which the conservation constraints and flux relationships can be deduced, either informally or through a rigorous analysis of the stoichiometric matrix. The initial analysis of a steady-state metabolic model is summarized in an algorithm. Key references to the literature on metabolic modelling are given.

Computer Simulation↗
PubMed1990

The development of a high-order Taylor expansion solution to the chemical rate equation for the simulation of complex biochemical systems.

A numerical method for evaluating chemical rate equations is presented. This method was developed by expressing the system of coupled, first-degree, ordinary differential chemical rate equations as a single tensor equation. The tensorial rate equation is invariant in form for all reversible and irreversible reaction schemes that can be expressed as first- and second-order reaction steps, and can accommodate any number of reactive components. The tensor rate equation was manipulated to obtain a simple formula (in terms of rate constants and initial concentrations) for the power coefficients of the Taylor expansion of the chemical rate equation. The Taylor expansion formula was used to develop a FORTRAN algorithm for analysing the time development of chemical systems. A computational experiment was performed with a Michaelis-Menten scheme in which step size and expansion order (to the 100th term) were varied; the inclusion of high-order terms of the Taylor expansion was shown to reduce truncation and round-off errors associated with Runge-Kutta methods and lead to increased computational efficiency.

Algorithms↗
PubMed1990

POLCA, a library running in a modern environment, implements a protocol for averaging randomly oriented images.

The library POLCA implements the averaging of biological structures whose images are recorded in digital form from electron micrographs. The averaging protocol is based upon a method developed about ten years ago, which allows one to operate on a sequence of objects oriented and displaced at random within their frame; the relative rotations and the displacements of the structures are detected with the use of correlation algorithms and modified to make all objects appear the same, apart from their noisy components. The average image is then obtained by a simple addition and the signal-to-noise ratio is improved by a factor equal to the square root of the number of objects used to calculate the average. With respect to the original implementation of the method, two novel features characterize the library: the first one deals with the functions that are cross-correlated to determine the relative rotations of the structures; the functions used here are the inverse transforms of the amplitude spectra (IAS functions), which give rise to sharp maxima when they are cross-correlated. The second peculiarity is the systematic adoption, in the transformations of coordinates and in other circumstances, of an interpolation technique based upon the Fourier series kernel. POLCA is written in C and runs on a VME machine under the UNIX V/68 operating system. A programming style has been adopted to exploit fully the machine resources.

Algorithms↗
PubMed1991

Building structural models of peptides: a semi-automatic software.

We present a software package that allows the construction and display of structural models of proteins starting from the amino acid sequence written in the one-letter code of standard data bank format. The software includes a very fast and efficient algorithm aimed at finding the global energy minimum of the potential function describing the molecular interactions. The whole package is conceived to have maximum flexibility. Completely automatic procedures are envisaged for standard problems. For non-standard problems, the construction procedure can be interactively adopted to meet with different options.

Algorithms↗
PubMed1991

Parallel computation and FASTA: confronting the problem of parallel database search for a fast sequence comparison algorithm.

We have parallelized the FASTA algorithm for biological sequence comparison using Linda, a machine-independent parallel programming language. The resulting parallel program runs on a variety of different parallel machines. A straight-forward parallelization strategy works well if the amount of computation to be done is relatively large. When the amount of computation is reduced, however, disk I/O becomes a bottleneck which may prevent additional speed-up as the number of processors is increased. The paper describes the parallelization of FASTA, and uses FASTA to illustrate the I/O bottleneck problem that may arise when performing parallel database search with a fast sequence comparison algorithm. The paper also describes several program design strategies that can help with this problem. The paper discusses how this bottleneck is an example of a general problem that may occur when parallelizing, or otherwise speeding up, a time-consuming computation.

Algorithms↗